The value of rituximab addition to chemotherapy treatment of real-world CLL patients: A 15 year single center experience

Background: The addition of the monoclonal antibody rituximab to chemotherapy has been shown to improve progression free survival and overall survival in prospective trials in CLL patients. However, CLL patients participating in clinical trials may not be fully representative of the overall patient population in clinical practice as there is selection due to study availability, willingness to participate and various in- and exclusion criteria. To date, the efficacy of rituximab added to standard chemotherapy in first line and relapsed CLL patients has been poorly validated in observational studies in unselected real-world CLL patients. Aims: To evaluate the efficacy of rituximab-chemotherapy (R-CTX) compared to chemotherapy (CTX) in a real-world CLL population. Methods: All patients from a large teaching hospital diagnosed with immunophenotypically confirmed CLL in the period from 1-1-2000 up to 1-9- 2015 were analyzed for this study and were categorized into two groups (1) those treated with CTX and (2) those who received R-CTX. The clinical outcome of patients was evaluated based on the “treatment-free interval” (TFI), defined as the time from stop of chemo(immuno)therapy to start of next treatment. Patients who did not need next treatment were censored at time of last followup or death. In addition, overall survival (OS) for patients treated in the period when rituximab had become available in our center was compared to patients treated before the rituximab era (before and after 1-1-2006, respectively). Results: A cohort of 375 CLL patients was studied, of whom 124 CLL patients (33%) required treatment in the observation period. The median age at firstline therapy was 67 years; 55% and 45% of these patients received first line CTX or R-CTX, respectively, and 47% of these patients required a second or later line of (R-)CTX. In total 221 treatment periods of (R-)CTX were studied with respect to treatment-free interval, 124 first-line, and 97 courses of retreatment. In the first-line treatment group 12 (10%) and 24 patients (19%) were treated with purine-analogue-based schedules without or with R respectively, i.e. (R-)fludarabine or (R-)fludarabine plus cyclophosphamide, 55 (45%) and 31 patients (25%) were treated with chlorambucil/CVP-based regimens without or with R respectively, and two patients (2%) were treated with CHOP and Rbendamustin. The median TFI for patients treated with CTX was 31 months (95%CI; 20 - 42 months) and was significantly better in the R-CTX group where the median TFI was not reached during the observation time (hazard ratio 0.40, 95%CI 0.22 - 0.73). In second or later lines of treatment 15 (15%) and 11 patients (11%) were treated with purine-analogue-based schedules without or with R respectively, i.e. (R-)fludarabine or (R-)fludarabine plus cyclophosphamide, 25 (26%) and 31 patients (32%) were treated with chlorambucil/CVPbased regimens without or with R respectively, and 15 patients (15%) were provided with other treatment modalities, i.e. (R-)CHOP or (R-)bendamustin. The median TFI for CTX was 27 months (95%CI; 18 - 52 months) vs 55 months for R-CTX (95%CI; 41 months - NR), HR 0.47 (95%CI 0.15 - 0.90) for subsequent lines. OS for patients treated in the R era was 48 vs 35 months for patients treated before the introduction of rituximab (p=0.02). Summary/Conclusions: Our study shows that the addition of rituximab improved treatment free interval in first- and subsequent lines and prolonged overall survival in a cohort of CLL patients receiving treatment in routine clinical 'real world' practice.